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Allogeneic Hematopoietic Stem Cell Transplant (HSCT) A potentially curative option that is primarily being used in younger patients with HLA-matched donors1,2,3

Correcting the Genetic Deficiency of TDT May Give Patients the Opportunity to Become Thalassemia-Free.1,2,3

Allogeneic hematopoietic stem cell transplant (HSCT) is an option that can potentially correct the genetic deficiency of transfusion‑dependent beta‑thalassemia (TDT). Allogeneic HSCT replaces the patient’s hematopoietic stem cells (HSCs) carrying the genetic mutations of beta‑thalassemia with those from a matched donor. Successful allogeneic HSCT can establish long‑term normal hematopoiesis and alleviate the need for transfusion and chelation in patients with TDT.1

Allogeneic HSCT is mostly limited to pediatric patients with an available matched sibling donor.1,3,4,5

  • On average, only 25-30% of patients have a matched sibling donor13
  • A retrospective non-interventional study of 1493 patients with thalassemia major who underwent allogeneic HSCT (between 2000 and 2010) estimated 2-year overall survival and thalassemia-free survival to be 88% and 81%, respectively
  • The use of donor cells in HSCT introduces the risk of potentially life‑threatening graft‑versus‑host disease (GvHD) and graft rejection4,5

Many patients with TDT do not receive allogeneic HSCT due to increased risk of mortality stemming from: 1,3,4,5

Lack of a suitable matched donor3
Presence of existing complications5
Age4

Survival Rates for 1493 HSCT Recipients With Thalassemia 
During the Period 2000-20104

Overall and thalassemia free survival rates after allogeneic hematopoietic stem cell transplantation
Overall and thalassemia free survival rates after allogeneic hematopoietic stem cell transplantation
Overall and thalassemia free survival rates after allogeneic hematopoietic stem cell transplantation

Overall Survival and Thalassemia-Free Survival Rates Are 
Highest in Thalassemia Patients With a Matched Sibling Donor4

Donor Type Overall Survival Rate*
(2 years post-HSCT)
Thalassemia-Free Survival Rate*
(2 years post-HSCT)
Matched Sibling Donor (n=1061) 0.91 ± 0.01 0.83 ± 0.01
Matched Related Donor (n=127) 0.88 ± 0.04 0.78 ± 0.05
Mismatched (n=57) 0.68 ± 0.11 0.68 ± 0.11
Unrelated Donor (n=210) 0.77 ± 0.03 0.77 ± 0.03

*p<0.001

HSCT: 30 Years of Enabling 
Thalassemia-Free Survival1

Allogeneic HSCT is a treatment option with potential to correct the genetic deficiency in TDT.1

HSCT is an accepted approach to treating TDT patients with an HLA-identical related donor or a well-matched unrelated donor. In patients for whom these are not available, the options of HLA-matched unrelated cord blood donors and HLA-mismatched related donors are being experimentally explored.1

Over 3000 HSCT procedures have been conducted worldwide for thalassemia major in the last three decades.1

Prior to HSCT1

Prior to HSCT, Thalassaemia International Federation (TIF) guidelines recommend the following:

  • Thorough pre-transplant evaluation with accurate iron studies, including cardiac iron/function, liver iron/function, and liver histology with assessment of fibrosis
  • Chelation treatment if needed to remove as much iron as possible (ideally, the patient has had good long-term iron control secondary to regular and effective chelation therapy)
  • Evaluation of pre-transplant endocrine dysfunction to provide a frame of reference for comparison during post-transplant follow up

Following HSCT1

After HSCT, Thalassaemia International Federation (TIF) guidelines recommend the following:

  • Close monitoring of hematological and engraftment parameters, infectious complications and graft-versus-host disease (GvHD) in the first year post-HSCT
  • Immunization in the second year post-HSCT if there is no GvHD
  • Removal of excess iron post-HSCT provided the graft is stabilized, the patient does not have chronic GvHD and is not taking any immunosuppressive treatment
  • Long-term follow-up to monitor potential development of multi-system problems like iron overload, pubertal development, and growth and endocrine deficiencies related to the primary disease
  • Follow-up and referral for patients experiencing endocrine dysfunction and infertility

Determining Transplant-Related Risk Factors 
in TDT Patients

Between 1980 and 2000, more than 1000 thalassemia patients underwent HSCT from HLA-identical
siblings in the transplant center of Pesaro. During this time, the Pesaro group developed a prognostic scheme
to predict transplant outcomes in patients less than 17 years of age. The three risk determinants in this
prognostic scheme were related to iron burden, and are as follows:1

  1. Lifetime quality of chelation received prior to transplantation (regular versus non-regular)
  2. Hepatomegaly (defined as more than 2 centimeters below the costal margin)
  3. Presence of liver fibrosis pre-transplant, as determined by hepatic biopsy examination

Based on these variables, patients are classified into three groups:1

black info icon To this day, outcomes of HSCT in patients with TDT are seen to be different for each of these groups.1,5

Mortality in Patients With an HLA-Identical Sibling Donor (MSD)5

CLASS I or II

CLASS III

The Use of Donor Cells in HSCT Introduces the Risk of Potentially Life-Threatening Graft-versus-Host Disease (GvHD) and Graft Rejection4,5


  • SEVERE ACUTE GvHD (GRADE III-IV)*

    9% (whole population)
    7% (patients with HLA-matched sibling donor)

  • LIMITED CHRONIC GvHD

    15% ± 1

  • EXTENSIVE CHRONIC GvHD

    6% ± 1


*Risk within first 100 days post-HSCT  2-year risk post-HSCT  P=0.001

Chronic GvHD assessment was done in 1140 patients who survived with a functioning graft for >100 days.

Overall Survival and Increased Mortality With Age4

In patients who received an HSCT from HLA identical sibling donors, overall survival (OS) and thalassemia-free survival (TFS) decreased with age. The threshold age for optimal transplant outcomes was around 14 years.4


Overall Survival and Thalassemia-Free Survival in Patients With Matched Sibling Donors (MSD)4

SWIPE OR ROTATE
 
Age
<2 years
2-<5 years
5-<10 years
10-<14 years
14-<18 years
≥18 years
P-value (for trend)
  Overall Survival Thalassemia-Free Survival
Number of Patients Events 2-year OS Events 2-year EFS
66 3 0.95 ± 0.03 4 0.93 ± 0.03
266 13 0.94 ± 0.02 32 0.86 ± 0.03
352 33 0.90 ± 0.02 52 0.83 ± 0.02
197 8 0.96 ± 0.02 24 0.86 ± 0.03
97 14 0.82 ± 0.04 20 0.74 ± 0.05
82 16 0.80 ± 0.05 18 0.76 ± 0.05
  <0.001 <0.001

Adapted from Baronciani D, Angelucci E, Potschger U, et al. Hematopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000–2010. Bone Marrow Transplant. 2016;51(4):536-541.

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“Showing this impact of age on transplant outcomes supports the argument that thalassemia is a progressive disease resulting in tissue damage and that deterioration starts early in a patient’s life, even in the era of oral chelation therapy.”

D Baronciani, et al., 20164

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Consider asking the parents of your pediatric TDT patients:

"Would you consider HSCT for your child with a matched sibling donor?"

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Actor portrayals throughout. Not real patients.

Take the Beta-Thalassemia Challenge

HSCT using a matched sibling donor (MSD) is associated with improved mortality and lower risk of immunological complications like graft-versus-host disease (GvHD). Approximately what percentage of patients have an available MSD?

B.

HSCT using an MSD is associated with decreased risk of immunological complications GvHD and graft rejection. It is also associated with decreased risk of mortality and improved overall survival rates. Unfortunately, only approximately 25-30% of patients have an available MSD.1,3,4,6

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